The neuroanatomical substrates of depression remain poorly understood. Studies of patients with stroke and tumors who develop affective disorder as well as studies of patients with late life depression point towards the involvement of structures such as the frontal cortex, caudate and putamen. During the first two years of this grant, considerable data has accumulated which also point towards the involvement of these structures. In addition, evidence has been accumulated suggesting a relationship between the hypercortisolemia seen in depression, neuroanatomical changes and cognitive deficits seen in depression. In this competing application, the focus is on characterizing functional and biochemical changes in the structures that the investigator has found are significantly affected in unipolar affective disorder patients. The study utilizes MRI for assessing volumes and proton spectroscopy for assessing physicochemical characteristics. The primary physicochemical hypothesis is that there will be increased CHO signal reflecting increased muscarinic activity. These methods provide a mechanism to closely examine the structures implicated. These studies are combined with clinical assessment, cognitive assessment and assessment of hypercortisolemia. The studies are likely to provide a better understanding of the neuroanatomical substrates of depression and the biochemical changes in depression. Further, they will provide a better understanding of the pathophysiology of hypercortisolemia in depression.